Any discussion of the background art throughout the specification should in no way be considered as an admission that such background art is prior art, nor that such background art is widely known or forms part of the common general knowledge in the field.
In the human, each optic nerve contains about 1,000,000 nerve fibres, which convey information from all parts of each retina to the brain. A fundamental design feature of the human visual system is the chiasm, which allows visual information from the left half of each retina, to proceed to the right half of the brain and from the right half of each retina to go to the left half of the brain. Each half of the retina corresponds to half the visual field, a so called hemifield. This arrangement allows each of the left and right halves of the visual brain to receive binocular information about a half of the visual field. Subsequent communication between the two halves of the brain, such as via the corpus callosum, allows the two halves of the visual field to be perceived as a whole.
The pupils of eyes have more functions than being a camera aperture that regulates the flux of light into the eye via a simple reflex mediated by parts of the midbrain. The added sophistication of pupillary function is in part derived from the inputs from various brain areas that contribute to the pupillary response including higher brain areas of the visual cortex. These many individual responses must be combined, or pooled, in some way in order to cause the pupils to respond to visual stimuli. FIG. 1A illustrates the afferent pathways (including optical nerves 2) from the two eyes 1 via the chiasm 3 to two pretectal olivary nuclei (PONs) 4, and then the efferent portion via a second chiasm to two Edinger-Westphal nuclei (EWN) 6 and then onto the cilary ganglia, and FIG. 1B at right shows a simplified version of these pathways.
The first site of combination of many component signals to give a single observed pupil response is the pretectal olivary nucleus (PON) 4. There is one PON on each side of the head, and each receives information from half of each of the two retinas 1. The two PONs 4 then convey information to both of the Edinger-Westphal (EW) nuclei 6, one on each side of the brain, which in turn innervate the pupils via the oculomotor nerves. This represents a so-called second decussation, that is to say a second chiasm. This circuitry means that each pupil receives information about the pooled activity of both retinas 1, and importantly, that either pupil can respond to stimulation to the left or right half of the visual field of either eye. Thus each pupil can independently provide information on the operation of both retinas 1. When a pupil gives a response to the retina of its own eye this is said to be a direct response. When a pupil responds to activity from the retina of its fellow eye that is said to be a consensual response. Importantly, at each stage of pooling, in the PON 4 or the EWN 6, there is the opportunity for visual processing, that may include gain control. Thus, in the pupil system, gain control may be separately controlled for each half retina or each half of the visual field.
About half the input to the PON is from melanopsin containing retinal ganglion cells (mcRGC) that come directly from the eye [for further information see P. D. Gamlin, “The pretectum: connections and oculomotor-related roles”, Prog Brain Res, 2006, Volume 151, Pages 379-405]. That work also describes the connectivity of the PON in detail. The nerve fibres of these and all the other types of retinal ganglion cells make up the optic nerve projecting from the eye to the brain. These mcRGCs are the neurons running from the eye to the PON illustrated in FIG. 1A. The mcRGCs have two separate types of responses to light [for further information see D. M. Dacey, H. W. Liao, B. B. Peterson, F. R. Robinson, V. C. Smith, J. Pokorny, K. W. Yau and P. D. Gamlin, “Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN”, Nature, 2005, Volume 433, Issue 7027, Pages 749-754]. The first response type derives from melanopsin that is present in the cell bodies and dendritic arms of these ganglion cells in the retina. Unlike the light responses of the photoreceptor cells of the retina the melanposin driven response of mcRGCs has no light adaptation mechanism and so increases steadily with increasing light level. The melanopsin pigment responds to blue light and the response itself is very slow, taking several seconds to respond to a transient increase in blue light. This slow integrative response is mainly responsible for the mean pupil size, smaller in bright light, more dilated in dim light.
As with all other types of retinal ganglion cells (RGCs), the mcRGCs also convey signals derived from rod and cone photoreceptor cells of the eye. The cone driven component responds positively to yellow light (luminance) and negatively to blue light. This response type is often referred to as a Yellow-ON/Blue-OFF class of response. These responses are much more transient maintaining the time resolution of the cones. This system also necessarily embodies the light adaptation mechanism possessed by the photoreceptors and cells that process photoreceptor information such as bipolar and horizontal cells before those signals are passed to the RGCs. Other types of retinal ganglion cells convey information to the brain about differential red and green content of images, and also, the luminance (brightness) information in images. The main luminance signals are conveyed to the brain by the parasol retinal ganglion cells. The red-green colour signal is carried by midget retinal ganglion cells. Together the parasol and midget cells make up the majority of the optic nerve fibres in humans and allied primates.
Most types of retinal ganglion cells, including parasol and midget cells, and also about half of the mcRGCs, proceed to the visual cortex via the lateral geniculate nucleus (LGN). The visual cortex is a massively interconnected set of visual processing areas. Many of these visual cortical areas are also multiply and reciprocally connected to the midbrain via the pulvinar areas [for further information see S. Shipp, “The functional logic of cortico-pulvinar connections”, Philos Trans R Soc Lond B Biol Sci, 29 Oct. 2003, Volume 358 (1438), Pages 1605-1624; and S. Clarke, S. Riahi-Arya, E. Tardif, A. C. Eskenasy and A. Probst, “Thalamic projections of the fusiform gyms in man”, Eur J Neurosei, May 1999, Volume 11 (5), Pages 1835-1838].
Higher centres within the extrastriate visual cortex then communicate with the PON providing about half its input nerve supply [again, see P. D. Gamlin, “The pretectum: connections and oculomotor-related roles”, Prog Brain Res, 2006, Volume 151, Pages 379-405]. Among the various signals computed in the cortex is distance information derived from the binocular disparity between the eyes. This controls the so called triad of responses that occurs when objects loom near to us, whereby the eyes verge inward, the lens of the eye accommodates, and the pupils constrict. Presumably, the pupil constriction aids near vision by increasing the depth of field. Obviously the accommodative triad requires information about depth and that information is provided to the PON by its binocular cortical inputs. The accommodative response is known to contain input from the luminance and red-green input systems mentioned above that also proceed to the PON via the visual cortex [for further information see F. J. Rucker and P. B. Kruger, “Accommodation responses to stimuli in cone contrast space”, Vision. Res, November 2004, Volume 44 (25), Pages 2931-2944]. The spectral colour sensitivity of the human luminance system is provided by the sum of red and green sensitive cone inputs, leaving the net peak spectral sensitivity corresponding to yellow hues.
Another input to the pupil that likely derives from the visual cortex are the pupillary responses to achromatic, equiluminant, high spatial frequency patterns, which permit visual acuity to be assessed via the pupillary responses, even in children [see J. Slooter and D. van Norren, “Visual acuity measured with pupil responses to checkerboard stimuli”, Invest Ophthalmol Vis Sci, January 1980, Volume 19 (1), Pages 105-8; or K. D. Cocker and M. J. Moseley, “Development of pupillary responses to grating stimuli”, Ophthalmic Physiol. Opt, January 1996, Volume 16 (1), Pages 64-67].
Therefore, the pupil has at least two possible sources of sensitivity to yellow luminance stimuli: the Yellow-ON response component of the mcRGCs and that of the parasol cells, the main constituents of the projection to the magnocellular layers of the LGN. The parasol RGCs have a rapid gain control mechanism that makes the parasol RGCs preferentially responsive to low spatial frequencies and high temporal frequencies [see E. A. Benardete, E. Kaplan and B. W. Knight, “Contrast gain control in the primate retina: P cells are not X-like, some M cells are”, Vis Neurosci, May 1992, Volume 8 (5), Pages 483-486]. The yellow-ON component of the mcRGCs does not seem to have such a gain control mechanism.
Overall, the diverse nerve supply to the pupil means that the pupil can potentially report on the activity of a large proportion of the optic nerve fibres, and various parts of the visual thalamus and cortex. These various parts of the visual nervous system can all affect one common form of visual testing done on human subjects, which is characterising the extent and function of the visual fields of the eyes.
Human visual fields are commonly assessed by static perimetry. The basic form of this assessment involves sequentially presenting small visual test stimuli one after the other to each of a pre-set array of locations across the visual field. During the test, subjects indicate subjectively whether or not the subjects have seen each test stimulus that the subjects have been presented with, whilst the subjects maintain their gaze on a fixation target for the duration of the test. For most perimeters, subjects give behavioural responses, such as button presses, to indicate when the subjects have detected a test stimulus. Component parts of the visual field can have characteristic visual abilities. The goal of perimetry is thus to assess the visual ability or abilities of each part of the measured portion of the visual field. This generalises to other sensory systems, such as pressure on the skin or temperature of the skin where the skin is tiled in sensory fields for each sensation, or audio-visual space, around a person. One may wish to make a map of which parts of the sensory field have normal, supernormal, or abnormal sensory function. A difference from normal performance at any sub-region of the visual field is often referred to as a deviation and if a particular deviating part of the field performs significantly worse than normal in some aspect then that test region is said to have a field defect.
Unrelated technologies are used to assess properties of the pupils of the eye, for example, devices that measure the static size of the pupil under particular viewing conditions are referred to as pupillometers and devices that monitor the changing size of pupils over time are referred to as pupillographs. The distinctions between such devices are outlined by the USA Food and Drug Administration. Pupillographs have previously been used in conjunction with standard perimetry stimuli to measure responses to those stimuli and provide perimetric maps of the visual fields. However, these systems have proved to be unreliable and have not achieved commercial form or acceptance.
There are many reasons to assess the visual fields. For example, the visual fields are fundamentally limited by physical features of the face, such as the nose, brow ridges, and cheek bones, which change during development. Therefore, assessing the visual fields can be useful for tracking facial development or examining if a normal person's facial features provide the person with a suitable visual field, for example, for use in certain sports or occupations. The visual nervous system continues to develop until adulthood and this can affect aspects of the visual field. Therefore, visual field testing can be used to determine the state of a young person's development. Physiological stress testing can also reversibly alter the visual fields. Therefore, the availability of a rapid mechanism or technique to test the visual fields before, during, and after the stress test is beneficial for stress level assessment. Visual field testing can also be useful in the management of disease rather than assisting in diagnosis per se. For example, a doctor could use repeated visual field testing over a period of some years to determine if a course of treatment was either preventing further decline of visual function, or whether some stronger intervention was needed. Visual field testing can therefore be used to assist in the management of a variety of visually dependent issues.
Similarly other diseases, such as glaucoma, can cause localised damage to smaller areas of the visual field. Again these diseases are amenable to current, and presumably future, treatments so visual field testing is useful to determine the effectiveness of treatment over time. Of course, this means visual field testing can be useful in providing data that would assist a physician, in conjunction with other data, to make a diagnosis of a disease such as glaucoma or other disease that affects the visual function of the subject. In the case of glaucoma, other data that would assist to confirm glaucoma, once a visual field defect had been observed with field testing, would include: eye pressure tests, measurement of the thickness of the nerve fibre layer of the retina by means of polarimetry or optical coherence tomography (OCT), and or the topography of the head of the optic nerve, often called the optic disc, by visual inspection, stereo fundus photography, OCT or confocal microscopy. These would normally be performed in conjunction with other tests such as magnetic resonance imaging, positron emission spectroscopy of the brain or electroencephalography, to eliminate brain-related sources of the visual field defect such as stroke.
Perimetry is also used in other eye diseases that might cause localised damage to the retina resulting in defective function within a patch of the visual field such as age-related macular degeneration (AMD) or diabetic retinopathy (DR). One objective is to determine if the patchy visual field defects correspond to any features observed on or in the retina observed with a fundus camera, optical coherence tomograph, or similar device. In addition to assisting a health professional to make a diagnosis, the outputs from perimetry and other measures can be used to determine the risk that a given eye might develop AMD or DR in future.
The primary drawback with existing static perimeter systems, however, is the subjective nature of the testing, which causes the tests to suffer from inaccuracies and human/patient error since the current tests rely on the patient's ability to respond behaviourally to their detection of a stimulus (static perimeters do not use pupillary responses). Typically, the patient has a limited window of time in which to respond to the stimulus and can only be presented with a limited number of stimuli within a practical test period. Therefore, if the patient is not concentrating, some false positive or false negative responses are delivered and the perimetry device is not able to establish visual sensitivity well, thus compromising the accuracy of the test. The test may also be compromised by the patient's inability, or lack of desire as in cases of malingering, to respond to the stimulus accurately, which may be caused by any number of variables for example whether the patient suffers from autism, age-related disorders, and drug impairment or intoxication to name a few.
A further disadvantage of current tests is the time in which a test may be completed. Since the patient must respond subjectively to each stimulus, this places a limit on the time in which the test may be conducted.
An objective alternate method for mapping the visual fields is to employ so-called multifocal methods. In these methods, one uses an array of visual stimuli, each member of the array being presented to a particular sub-region of the visual field. The appearance or non-appearance of stimuli at each sub-region of the visual field is modulated by temporal sequences that are mutually statistically independent. Optimally, the modulation sequences should be completely statistically independent, that is the modulation sequences should be mutually orthogonal, which is to say having zero mutual correlation. A variety of patents related to various orthogonal sequences [see U.S. Pat. No. 5,539,482 (U.S. Ser. No. 08/025,423) issued 23 Jul. 1996 to T. L. Maddess & A. C. James, the disclosure of which is wholly incorporated herein by reference] and near orthogonal sequences [see for example U.S. Pat. No. 4,846,567 (U.S. Ser. No. 06/893,789) issued 11 Jul. 1989 to Sutter] exist, but recent analysis methods permit more general stimuli to be used [see, for example: U.S. Pat. No. 6,315,414 (U.S. Ser. No. 09/647,357) issued 13 Nov. 2011 to T. L. Maddess & A. C. James; U.S. Pat. No. 7,006,863 (U.S. Ser. No. 10/239,971) issued 28 Feb. 2006 to T. L. Maddess & A. C. James; and International (PCT) Patent Publication No. WO/2005/051193 (PCT/AU2004/001656) published on 9 Jun. 2005 in the names of The Australian National University, T. L. Maddess & A. C. James; the disclosures of the three documents are wholly incorporated herein by reference).
The basic idea of multifocal methods is that the temporal statistical independence of the stimuli permits trains of many stimuli to be presented concurrently to different parts of a sensory field, for example at different regions of the visual field, or different stimulus conditions, each driven by its own sequence. Then the estimated responses to presentations at all the test locations, which may be one or more so-called weighting functions, may be recovered from recordings of pooled neural activity of the visual nervous system. The weighting functions can characterise linear responses and non-linear responses and interactions. The neural responses to the stimuli can be recorded by electrical or magnetic detectors, changes to the absorption, scattering or polarization of infrared light or other electromagnetic radiation from parts of the nervous system, or functional magnetic resonance imaging. As can be appreciated, sensors for detection of such neural responses are complex and rely on correct placement for efficient operation, typically on or near the scalp or eye of the patient. Also, methods such as electroencephalography suffer from the fact that different subjects have different brain anatomy and this affects the signals measured on the scalp. Subjects are also often averse to the placement of electrodes on their scalp or eyes, and there are health risks associated with any such contact method. Responses to the stimuli may be detected through monitoring of the pupils, which have the advantage of permitting non-contact assessment, but to date there are no commercial perimetry systems that use pupillography to do multifocal testing of the nervous system.
The following description summarises features of multifocal methods that make multifocal methods distinctive. U.S. Pat. No. 5,539,482 discloses the use of independent multifocal stimuli to be presented to the two eyes in order to determine responses generated in the brain just after the point where the inputs from the two eyes first come together, that is just after the first optic chiasm, using so called binocular interaction kernels. No other spatial or temporal constraints on those multifocal stimuli are made. U.S. Pat. No. 7,006,863 discloses that a particular temporal constraint is optimal. In particular, U.S. Pat. No. 7,006,863 discloses that presentations of transient valid stimuli at any location in the multifocal stimulus array should be interleaved with longer aperiodic sections of non-valid, null, stimuli, such that the mean rate of presentations of the valid stimuli at any one region of the stimulus ensembles is between 0.25 and 6 presentations per second. This means on any time step in the temporal stimulus sequence the probability of a valid stimulus appearing at a given single locations is, psingle, which is <<½. Since no constraint is made on when any two spatially adjacent neighbouring regions should appear relative to each other, two spatially adjacent neighbouring regions co-appear at probability=ppair, which is exactly equal to psingle×psingle=p2single. These multifocal stimuli are said to be temporally sparse. International (PCT) Patent Publication No. WO/2005/051193 applies a further constraint that when a stimulus appears at a given location that the probability of a spatially adjacent stimulus appearing, ppair, is <<p2single, and preferably ppair=0 for adjoining stimulus regions. These stimuli are said to be spatially-sparse, since immediately adjacent neighbouring stimuli either tend not to co-appear, or never co-appear. In all of the above three methods, the stimuli can be seen to be presented rather evenly across the visual field, particularly in the case of the spatially-sparse stimuli, and almost never, or never, occur in volleys of spatially adjacent clusters of stimuli.
Overall, a need exists for a rapid objective, non-contact visual field assessment, which can also be used for other purposes such as determining the focus of localised visual attention, and or interactions between other sensory fields and the visual field, for example the auditory field, or the somatosensory field.